PHOSPHONATE DIESTER AND PHOSPHONAMIDE SYNTHESIS - REACTION COORDINATEANALYSIS BY P-31 NMR-SPECTROSCOPY - IDENTIFICATION OF PYROPHOSPHONATEANHYDRIDES AND HIGHLY REACTIVE PHOSPHONYLAMMONIUM SALTS

A series of phosphonochloridates was prepared from the corresponding p hosphonate monoesters, and their reactions with alcohols, amines, and the bisnucleophile 4-aminobutan-1-ol have been investigated using P-31 NMR spectroscopy. In the conversion of phosphonate monoesters to phos phonochloridates via the addition of thionyl chloride or oxalyl chlori de, pyrophosphonate anhydrides were found to be formed readily as bypr oducts. The anhydrides reacted readily with alcohols, but more slowly than the corresponding phosphonochloridates, and only sluggishly, if a t all, with amines. Therefore, when phosphonamides are prepared, anhyd ride formation must be suppressed. This is accomplished when the monoe ster is added to the chloridating agent. Unhindered phosphonochloridat es reacted predominantly with the amino function of 4-aminobutan-1-ol to furnish the phosphonamidates, whereas a sterically hindered phospho nochloridate demonstrated a preference for O-coupling. This result ind ictes that the energy gained during P-O bond formation surmounts the k inetic barrier resulting from steric hindrance more effectively than f ormation of the weaker P-N bond. Importantly, treatment of the phospho nochloridates with tertiary amines prior to addition of the nucleophil e resulted in the formation of hitherto unrecognized phosphonylating a gents, which we formulated as phosphonyltrialkylammonium salts. The la tter, unlike the anhydrides, are more reactive than the phosphonochlor idates toward both alcohols and amines, affording improved yields of p hosphonate esters and amides. These improved yields are not obtained w hen triethylamine is added simultaneously with the nucleophile merely to neutralize acid rather than as a deliberate step to generate the ph osphonyltrialkylammonium salts. Use of these novel phosphonylating age nts proceeded without concomitant racemization at stereogenic centers alpha to phosphorous. Interestingly, reaction of even an unhindered ph osphonyltriethylammonium salt with 4-aminobutan-1-ol favored O-phospho nylation over N-phosphonylation by a factor of 8, demonstrating that b oth the charge transfer in the transition state and steric hindrance a ffect the propensity for P-O vis a vis P-N bond formation. In marked c ontrast, simultaneous addition of this bisnucleophile and triethylamin e, like coupling in the absence of tertiary amine, afforded the phosph onate and phosphonamide in nearly equal amounts.